Sperm 'switch' could lead to new fertility treatments

Scientists have discovered the "switch" that activates sperm cells to travel to the egg, potentially paving the way for new methods of male contraception and infertility treatment. The research is published in the journal Science.

Sperm cells cannot move far without a progesterone trigger.

According to the Centers for Disease Control and Prevention (CDC), in 2002, 7.5% of all sexually experienced men under 45 years of age, or 3.3-4.7 million men, had consulted a fertility doctor at some time.

Out of these, 18% were diagnosed with a male-related infertility problem, 14% of which related to sperm or semen.

Sperm cells are not very mobile. They have limited movement in the male reproductive tract. In fact, they are unable to reach the egg in the female tract unless they are activated by the hormone progesterone. It is the release of this hormone by the egg that triggers their journey.

In order for the sperm cell to increase mobility, calcium must also pass through its outer membrane and enter the "tail," or flagella, which it uses to propel itself along.

For the calcium to enter, a sperm protein known as CatSper needs to join with similar proteins in the flagella. If this process does not happen, the sperm will not be able to reach the egg.

In the current study, researchers wanted to find out whether progesterone interacts directly with CatSper to trigger the calcium influx, or if it acts on another molecule, which would then act on CatSper.

Isolating ABHD2 protein, step by step

Melissa R. Miller and colleagues - from the University of California-Berkley, the University of California-San Francisco and Yale University School of Medicine in New Haven, CT - set out to pinpoint exactly what triggers the movement of the sperm.

The team first exposed sperm to a chemical that inhibits a particular class of enzyme, because they suspected that the molecule that acts on CatSper might feature within that class of enzymes.

Next, they exposed the sperm to progesterone. They noted that the sperm remained inactive, suggesting that CatSper was not directly involved in the process.

Eventually, using modified progesterone, the team isolated the enzyme alpha/beta hydrolase domain containing protein 2 (ABHD2) from the sperm tails.

To test whether this was the target protein, the researchers inactivated ABHD2, before exposing it to progesterone. With the ABHD2 inactivated, progesterone was unable to activate the sperm cells.

This confirms that ABHD2 is the molecule to which progesterone must bind.

The authors conclude: "Progesterone-activated endocannabinoid depletion by ABHD2 is a general mechanism by which progesterone exerts its genome-independent action and primes sperm for fertilization."

Stuart Moss, PhD, director of the male reproductive health program at the National Institutes of Health's (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), which funded the study, says:

"This is an important advance in explaining how sperm become hypermotile in the female reproductive tract. Developing new compounds that block ABHD2 ultimately may yield new contraceptive methods to prevent sperm from reaching the egg."

The findings may give hope to people affected by infertility due to low sperm mobility. Treatments could focus on bypassing or enhancing ABHD2.

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